There are many situations where it is therapeutically desirable to increase the amount of tear fluid produced by the eye. Dry eye disease is the general term for indications produced by abnormalities of the precorneal tear film characterized by a decrease in tear production or an increase in tear film evaporation, together with the ocular surface disease that results. Approximately 38 million Americans are affected with some type of dry eye disorder. Dry eye disease includes keratoconjunctivitis sicca (KCS), age-related dry eye, Stevens-Johnson syndrome, Sjogren's syndrome, ocular cicatrical pemphigoid, blepharitis, Riley-Day syndrome, and congenital alacrima. Dry eye disease can also be caused by nutritional disorders or deficiencies (including vitamins), pharmacologic side effects, eye stress and glandular and tissue destruction, environmental exposure to smog, smoke, excessively dry air, airborne particulates, autoimmune and other immunodeficient disorders, and comatose patients who are unable to blink.
Corneal transparency is essential for the maintenance of visual function and is contingent on the flawless integrity of all its components: the epithelium, stroma, and endothelium. Disruption of the epithelial anatomic barrier activates healing and remodeling processes, which can predispose the tissue to stromal ulceration and/or cause stromal opacification, ultimately leading to irreversible visual deficit. Corneal injury is caused by any insult to the ocular surface: infection, trauma, chemical burns, contact lens wear, topical drug abuse, and postoperative damage. Dry eye can also cause corneal injury. Despite the numerous studies published in recent years that have indicated that cytokines, growth factors, and neuorpeptides can influence the epithelial proliferations and differentiations in vitro, a precise therapeutic approach to modulate the healing process has not yet been defined.
A healthy precorneal tear film has several important functions: 1) to protect the cornea from desiccation; 2) to aid in the immune response to infections; 3) to enhance oxygen permeation into the cornea; 4) to allow gliding movement of the eyeball and eyelids; and 5) to help maintain the ocular pressure through osmosis. There are two structures responsible for maintaining the properties of the tear film--the lacrimal glands and the conjunctiva (the mucous membrane which surrounds part of the eyeball and inner eyelids). These structures maintain the tear film via regulation of water and electrolyte transport and via mucin release by goblet cells.
The progression of dry eye disease is characterized by four main steps. The first step is a decrease in tear production. In rabbit models, this decrease in tear production has been shown to correlate with an increase in tear osmolarity. The second step is a loss of mucous-containing conjunctival goblet cells. This decrease in goblet cell density becomes evident several weeks after the onset of decreased tear production. The third step in the progression of dry eye disease occurs about 1 year later when desquamation of the corneal epithelium is observed. The fourth and last step of the disease is a destabilization of the cornea-tear interface (Gilbard, CLAO Journal 22:141-45 (1996)).
Currently, the pharmaceutical treatment of dry eye disease is mostly limited to administration of artificial tears (saline solution) to temporarily rehydrate the eyes. However, relief is short-lived and frequent dosing is necessary. In addition, artificial tears often have contra-indications and incompatibility with soft contact lenses (Lemp, Cornea 9: S48-550 (1990)). The use of phosphodiesterase inhibitors, such as 3-isobutyl-1-methylxanthine (IBMX) to stimulate tear secretion is disclosed in U.S. Pat. No. 4,753,945. The effectiveness of these phosphodiesterase inhibitors is currently being investigated (Gilbard, et al., Arch. Ophthal, 109:672-76 (1991) and 112:1614-16 (1994); idem, Inv. Ophthal. Vis. Sci. 31:1381-88 (1990)). Stimulation of tear secretion by topical application of melanocyte stimulating hormones is described in U.S. Pat. No. 4,868,154.
In addition, a topical ophthalmic formulation of cyclosporine (Restasis) has been investigated as a treatment of immune-based dry eye disease (Stern et al., Adv. Exp. Med. Biol., 438:643-651 (1998)). Stimulation of ocular mucin secretion has also been demonstrated with hydroxyeicosatetraenoic acid derivatives (Yanni, et al., U.S. Pat. No. 5,696,166), gefarnate (Nakamura et al., Exp. Eye Res., 65:569-574 (1997)). U.S. Pat. No. 5,900,407 and WO 98/34593 (Yerxa et al.) disclose a method of stimulating tear secretion from lacrimal tissue by administering to the eyes an effective amount of purinergic receptor agonists such as uridine 5'-triphosphate, cytidine 5'-triphosphate, adenosine 5'-triphosphate, dinucleotides, and their analogs. Jumblatt and Jumblatt (Exp. Eye Res., 67:341-346 (1998)) demonstrate the effects of adenine analogues on secretion of high molecular weight, mucin-like glycoprotein by conjunctival goblet cells.
Mucus is a viscous, lubricating material that recruits and maintains moisture to the surfaces it coats. Mucus is actively secreted with salt and water onto surfaces that require these hydrating and lubricating properties for normal functioning (Forstner et al., Adv. Exp. Med. Biol. 144:199-224 (1982)). Mucus is particularly important in the normal functioning of the ocular surface.
Goblet cells are the primary cell type responsible for secreting gel-forming mucins in epithelial tissues; they secrete mucin in response to neural stimulation. In the eye for example, mechanical stimulus of the cornea causes goblet cell mucin secretion, presumably via neurotransmitter release (Kessler, et al., Adv. Exp. med. Biol. 350:393-8 (1994)). It is known that P2Y.sub.2 receptor agonists, such as ATP, cause mucin secretion and that mechanical stimulus of the cornea triggers local ATP release (Jensen et al, poster presentation at American Academy of Optometry annual meeting, December, 1999, Seattle, Wash.). In addition, neurotransmitters, such as epinephrine, phenylephrine, serotonin, dopamine and vasoactive intestinal peptide (VIP), cause mucin secretion when topically applied to the eye.
Secretion from lacrimal glands, is under neural control of the parasympathetic and sympathetic efferent nerves that innervate the secretory acinar cells of the glands. These nerves contain the parasympathetic neurotransmitters acetylcholine and vasoactive intestinal peptide, which are believed to stimulate secretion of salt, water and protein via activation of muscarinic receptors that increase intracellular calcium concentration in the acinar cells (Dartt, p.1 -9, in Lacrimal Gland, Tear Film, and Dry Eye Syndromes, Ed. Sullivan, Plenum Press, New York, (1994)).
Muscarinic acetylcholine receptor agonists have thus been targeted towards Sjogren's syndrome related dry eye and dry mouth. Pilocarpine, a non-selective muscarinic agonist, is used systemically for dry eye and dry mouth under the trade name Salagen.RTM.. The topical ophthalmic formulation of pilocarpine is not useful for dry eye because it causes spasm of accommodation. This miotic, neuromotor effect is useful instead for lowering intraocular pressure in glaucoma patients (Leino and Urtti, P. 245-247, in Ocular Therapeutics and Drug Delivery, A Multidisciplinary Approach, Ed. I. K. Reddy, Technomic Publishing, Lancaster, Pa. (1996)).
Nicotinic acetylcholine receptors (nAChRs), present in a variety of tissues, are heterologous receptors made up of several subunits. Various nAChR subtypes exist and they show a complex regulation of calcium concentration and mediation of neurotransmitter (e.g. dopamine) release.
Nicotinic agonists have many pharmacological actions when applied locally or systemically, and synthetic compounds are being targeted towards a number of therapeutic indications including: Alzheimer's disease, Parkinson's disease, smoking cessation, epilepsy, neuroprotection, attention deficit disorder and pain (Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities, Eds. Arneric and Brioni, Wiley-Liss, Inc. (1999)). Nicotinic agonists, such as nicotine, stimulate the secretion of mucus when applied to the mucosal surfaces of the lung and stomach, and is believed to have protective effects on ulcerative colitis presumably by increasing colonic mucin secretion (Morris, et al., J Clin Gastroenterol, 27: S53-63 (1998), Finnie, et al., Clin. Sci., 91:359-364 (1996), Zijlstra, et al., Gut, 35:247-251 (1994); Kaunitz, et al., J Pharmacol. Exp. Ther., 265:948-954 (1993)). Transdermal nicotine has been used clinically as therapy for ulcerative colitis (Pullen, Ann. R. Coll. Surg. Engl. 78:85-91 (1996)).
The nicotine-associated effects of cigarette smoking have been studied extensively and it is well established that tobacco smoking leads to chronic bronchitis and mucus hyper secretion (Coles, et al., Am. J Pathology, 94:459-471 (1979); Wanner, et al., Am. J Respir. Crit. Care Med., 154:1868-1902, (1996). "Topical" tobacco smoke causes mucin secretion from airway goblet cells and systemic nicotine causes increased tracheal mucus secretion (Kuo, et al., Am. J Physiol. 263: L161-167 (1992); Lang, et al.; Klin. Wochenschr. 66:170-179 (1988); Hummer, et al., Klin. Wochenschr. 66:161-169 (1988), Richardson, et al., Eur. J Respir. Dis. Suppl. 153:43-51 (1987)). These pro-secretory effects of nicotine have been largely thought of as deleterious, with the exception of the association of less frequent ulcerative colitis among cigarette smokers.
Recent advances in the field of nicotine receptors has revealed that it is possible to create ligands for specific nicotinic receptor subtypes, thereby reducing or eliminating altogether the unwanted side effects of nicotine, such as neuromotor and cardiovascular effects (Brioni et al., Behav. Neural. Biol. 59:57-62 (1993); Brioni, et al., Adv. Pharmacol. 37:153-214 (1997)) The field of therapeutic nicotinic agonists largely focuses on the central nervous system effects of nicotinic agonists and their ability to stimulate cognition (U.S. Pat. Nos. 5,922,723 and 5,861,423). The mild antiinflammatory effects of nicotine are established; smokers have been shown to have a lower incidence of inflammatory diseases such as ulcerative colitis, sarcoidosis, pigeon breeder's disease, fanner's lung, allergies, endometriosis, uterine fibroids and acne (Amie & Grioni Ch. 11, p. 205). Nicotine has also been investigated for its effects on CNS inflammation (Brioni, et al., (1997), supra) based diseases.
It is known that nicotine from tobacco smoke lowers ocular blood flow (Novack, Curr. Opin. Ophthalmol., 5:110-4 (1994)) and that nicotinic receptors are located in the retina (Wakakura, et al., Arch. Clin. Exp. Ophthalmol., 236:934-9, (1998); Baldridge, J Neurosci., 16:5060-72, (1996)), but the effects of nicotinic agonists on ocular surface hydration and lubrication is unknown. Nicotine has been added to the ocular and oral mucosal surfaces to evaluate effects on sensory neuron-mediated irritation responses (Carstens, et al., J Neurophysiol., 80:465-92 (1998)).
Because of the ability of nicotinic agonists to stimulate secretion in the lung and gastrointestinal tract, Applicants were motivated to investigate whether nicotinic agonists could effect hydration and lubrication of the ocular surface, and thus be effective in treating dry eye diseases and disorders of impaired hydration and lubrication. Applicants have found that nicotinic receptor agonists, when given topically or systemically, provide a therapeutic effect of treating dry eye disease by increasing the hydration and lubricating properties and reducing inflammation of ocular surfaces. The present invention may also be useful as a wash or irrigation solution in conscious individuals, during surgery for treating corneal wounds, or to maintain comatose patients or those who cannot blink due to neuromuscular blockade or loss of the eyelids.